tbuckley/cabot-search huggingface dataset:
VEGF inhibitors (VEGFi) activity in liver metastases (mets) regardless of primary cancer type: Meta-analysis and systematic review.
Authors: Ines Esteves Domingues Pires Da Silva, Serigne N. Lo, Jordan W. Conway, Richard A. Scolyer, Matteo S. Carlino, Alexander M. Menzies, Georgina V. Long
Journal: Journal of Clinical Oncology (2022)

3024 Background: Liver metastasis is a poor prognostic factor in several cancers and is associated with poor response to immunotherapy (IO) in melanoma and lung cancer. VEGFi have activity in hepatocarcinoma (HCC) and is hypothesized to be due the hypoxic microenvironment. Whether this is also true for liver mets is unknown. We sought to assess the efficacy of VEGFi in liver mets utilizing randomized-controlled clinical trials (RCTs) testing the efficacy of VEGFi, regardless of primary cancer site. Methods: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to January 1, 2022. All RCTs that compared a backbone of systemic therapy (chemotherapy [chemo] and/or IO and/or targeted therapy [TT]) or best supportive care (BSC) with vs without VEGFi in patients (pts) with liver mets from any cancer were selected. HCC trials were excluded. Study design, cancer type, number of pts, lines of treatment, study drugs and hazard ratios (HRs) with 95% CIs for overall survival (OS) and progression-free survival (PFS) were extracted. Pooled effects of VEGFi in pts with liver mets across different cancer types were estimated using random effect model with inverse variance. Heterogeneity between studies was assessed by I 2 statistics. Sensitivity analyses were performed considering prespecified subgroups of trials. Results: 3170 pts with liver mets from 19 RCTs were included in this meta-analysis: 8 colorectal cancer, 4 non-small cell lung cancer, 4 renal cell cancer &amp; urothelial cancer, 1 pancreatic cancer, 1 GIST and 1 gastric cancer. Backbone systemic therapy in these trials included: chemo (11), TT (2), IO (2), chemo+IO (1), chemo+TT (1); and 2 BSC trials. Moderate heterogeneity between studies for both PFS (I 2 = 55%) and OS (I 2 = 46%) was seen. The addition of VEGFi to standard systemic therapy or BSC was associated with superior PFS (HR = 0.61; 95% CI, 0.50-0.74; p &lt; 0.0001) and OS (HR = 0.86; 95%CI, 0.76-0.99; p = 0.0334) in pts with liver mets, regardless of whether pts had only liver mets or concurrent other sites of mets. In the subset of RCTs with data on pts without liver mets, the benefit with VEGFi was more pronounced in patients with liver mets (HR = 0.56) vs those without liver mets (HR = 0.64) for PFS, but not for OS. Conclusions: The addition of VEGFi to standard management improved survival outcomes in pts with liver mets across different cancer types and warrants further investigation. VEGFi added to IO may be effective in pts with resistant liver mets.
Distinct biosignatures associate with survival after chemoimmunotherapy in a randomized, three-arm phase II study in patients with metastatic pancreatic cancer.
Authors: Lacey J. Padrón, Deena M. Maurer, Mark H. O'Hara, Eileen Mary O'Reilly, Robert A. Wolff, Zev A. Wainberg, Andrew H. Ko, George A. Fisher, Osama E. Rahma, Jaclyn P. Lyman, Christopher R. Cabanski, Jia Yu, Shannon M. Pfeiffer, Marko Spasic, Travis J Hollmann, Richard Chen, Jill O'Donnell-Tormey, Samantha Bucktrout, Theresa LaVallee, Robert H. Vonderheide
Journal: Journal of Clinical Oncology (2022)

4010 Background: Preclinical and small clinical studies of chemoimmunotherapy for metastatic pancreatic ductal adenocarcinoma (mPDAC) point to a yet unrealized potential of clinically significant immune activation. In our phase II study of the CD40 agonist antibody sotigalimab (sotiga) and/or nivolumab (nivo) with gemcitabine and nab-paclitaxel (chemo), we observed promising improvements in overall survival (OS) in 105 patients with newly diagnosed mPDAC (NCT03214250); the primary endpoint of 1-year OS rate was 57.7% (p = 0.006) in the nivo/chemo arm, 48.1% (p = 0.062) in the sotiga/chemo arm and 41.3% (p = 0.233) in the nivo/sotiga/chemo arm (O’Hara, ASCO 2021) as compared to a historical control of 35%. Here, we report results of multi-omic translational analyses designed to identify signatures predictive of OS benefit. Methods: Longitudinal blood and tumor tissue samples were collected for immune and tumor biomarker analysis. Tumor samples underwent RNA sequencing and multiplex immunofluorescence (mIF). Peripheral blood was analyzed by mass cytometry time of flight (CyTOF), high parameter flow cytometry, and proteomics. Machine learning (ML) algorithms were applied to the data to identify biosignatures related to OS in each arm. Results: Comprehensive multi-omic, multi-parameter immune and tumor biomarker analyses identified distinct pretreatment immune signatures predictive of longer OS specific to nivo/chemo or sotiga/chemo (Table, representative examples). Because patients in each arm received chemotherapy, these and other arm-unique biomarkers suggest a relationship to the immunotherapy rather than chemotherapy in this randomized study. There was evidence of immune exhaustion in the sotiga/nivo/chemo arm that may explain the lack of survival benefit. Conclusions: From in-depth translational and ML analyses of randomized phase II trial of first-line chemoimmunotherapy in mPDAC patients, we identified novel biomarkers that associated with OS distinctly in each arm. Clinical trials in first-line mPDAC exploiting these previously unappreciated biomarkers and aiming to enrich patients for response, are warranted to further advance chemoimmunotherapy in this disease. Clinical trial information: NCT03214250. [Table: see text]
Exploratory analysis on crosstalk between intra-tumor immunity and FGF/FGFR pathway in clear cell renal cell carcinoma.
Authors: Takafumi Narisawa, Sei Naito, Yoshihide Mitsuda, Rintaro Oe, Hidenori Sato, Chizuru Kobayashi, Mizuki Fukuda, Takumi Kitaoka, Yuki Miyano, Hiromi Ito, Mizuki Kimura, Makoto Hamaguchi, Ken Aoshima, Mitsuru Futakuchi, Norihiko Tsuchiya
Journal: Journal of Clinical Oncology (2022)

e16525 Background: Clear cell renal cell carcinoma (ccRCC) patients classically show good response to VEGFR inhibitors; however, the biological basis by which FGFR inhibition provides tumor response was not well understood. Here, we performed an exploratory analysis of the relationship between the FGF/FGFR pathway and intra-tumor immunity to support the effectiveness of FGFR inhibitors for ccRCC. Methods: We used whole transcriptome data and immunohistochemistry with metastatic clear cell RCC specimens from patients who were treated at the Yamagata University Hospital (n = 57). FFPE samples were prepared from the primary lesions of treatment-naive metastatic ccRCC patients. FFPE was sliced by a pathologist to evaluate the immunological microenvironment. RNA extraction and immunostaining were performed at the same site. Immuno-histological quantification was performed by automatically analysis system HALO in digital whole slide imaging. Hierarchical clustering was performed, and the cohort was divided based on the profile of the FGF and immune cells. We analyzed the cancer-specific survival based on the FGF cluster classification and investigated the relationship between FGF-FGFR expression and immune cell infiltration that were evaluated histologically. Results: RNA transcriptome data showed that FGF2 and FGF7 were widely expressed in ccRCC. Hierarchical cluster analysis based on the FGF expression profile (intrinsic FGFs were excluded) revealed that metastatic ccRCC had three distinct patterns. Cluster1 showed low FGFs expression, except for FGF2 and 7, while Cluster2 and 3 expressed multiple FGFs. Survival analysis showed Cluster2and 3 had a poor cancer-specific survival rate than Cluster1 (Logrank test, p = 0.05). However, no association was detected between the FGF cluster classification and the infiltration of immune cell count in immunohistological analysis. In comparison of the expression of each FGF subfamily and the positive cells of CD4, CD8, CD68 and CD31 (Mann–Whitney U test, p &lt; 0.05), CD4 and CD8 were higher in the cases expressing FGF20. While most FGF subfamilies have been suggested to be less associated with immune cell infiltration (excluding FGF20), further analysis among FGF receptor expression and immune signatures are ongoing. Conclusions: Our study demonstrates the possibility of intra-tumor interaction between FGF/FGFR axis and immune infiltration in ccRCC.
Addressing Latinx CANcer Care Equity (ALCANCE) randomized controlled trial: Precision medicine and community health workers.
Authors: Gladys M. Rodriguez, Emily H. Wood, Maria Leach, Gerardo Villicana, Ariana Murillo, Lisa G. Rosas, Ysabel Duron, Dale G. O'Brien, Zach Koontz, Manali I. Patel
Journal: Journal of Clinical Oncology (2022)

TPS1601 Background: Cancer mortality has declined over the past decade due to clinical advances including precision medicine. Despite these clinical advancements, low-income and racial/ethnic minorities experience worse cancer morbidity and mortality. Specifically, these populations have lower rates of genomic testing and are significantly underrepresented in precision medicine research. Community-based, culturally tailored approaches are needed to address these ongoing disparities. The objective of this randomized controlled trial is to test whether a community health worker (CHW)-led intervention can improve patient understanding of precision medicine topics and delivery of evidence-based cancer care more than usual cancer care alone. Methods: We developed a county-wide cancer care initiative and a community advisory board (CAB) comprised of patient, caregiver, payer, clinician, and governmental stakeholders in Monterey County—comprised of 60% Latinx, non-English speaking, immigrant populations. As guided by the CAB, we developed a CHW-model to provide education on precision medicine and screen for complications of social determinants of health in 1:1 discussions with patients. In collaboration with a local community oncology clinic, we plan to randomize 110 patients with cancer who are receiving active treatment into usual care or usual care plus the CHW-led intervention. Inclusion criteria includes patients who are: 1) 18 years of age or older; 2) racial/ethnic minorities; 3) low-income; 4) uninsured or insured by Medicaid and/or local agricultural employers; and 5) speak English or Spanish. Exclusion criteria includes: 1) lack capacity to consent to study procedures; 2) plan to move from the area within a year. We will measure the effect of the intervention on patient knowledge of precision medicine using a survey adapted from Davies et al. Secondary outcomes include effect on health-related quality of life using the Functional Assessment of Cancer Therapy – General, patient activation using the Patient Activation Measure, satisfaction using the Satisfaction with Decision Scale, prognosis and treatment preferences using an adapted survey by Weeks et al., healthcare utilization, and receipt of evidence-based cancer care. We will administer surveys at baseline, 3-, 6- and 12-months post-enrollment. To date, 67 participants have been enrolled. This study will show if CHW-models increase knowledge of precision medicine in this population. Clinical trial information: NCT04843332.
Beyond gemtuzumab ozogamicin: A systematic review of antibody therapies for acute myeloid leukemia.
Authors: Vikram Sumbly, Ian Landry, Qamar Iqbal, Mohammad Ebad Ur Rehman, Asmi Chattaraj, Zobia Aijaz, Zoia Ehsan Khattak, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e19006 Background: Acute myeloid leukemia (AML) is a neoplasm that is defined by the uncontrolled growth of myeloid progenitor cells. It is the most common form of acute leukemia in adults and is associated with poor outcomes in patients ≥ 75 years. Multiple antibody-drug conjugates (ADCs) are being investigating for their benefits in AML. Methods: A search was performed on PubMed, Cochrane, Scopus, Web of Science and ClinicalTrials.gov using the PRISMA guidelines. After screening 1,806 articles, a total of eight studies were included for this review. Results: Montesinos et al. gave a combination of talacotuzumab (anti-CD123 antibody) + decitabine to AML patients and reported an ORR of 27% (42/157) in the talacotuzumab + decitabine arm. Uy et al. studied flotetuzumab (anti-CD3 x anti-CD123 DART) and reported an ORR of 30% (9/30) in patients treated at the recommended phase two dose. Ho et al. noticed a CR in 26% (30/117) of patients who received a combination of vadastuximab talirine (anti-CD33 ADC) with azacytidine/decitabine. Feldman et al. observed that the ORR was higher in the lintuzumab (anti-CD33 antibody) + chemotherapy arm than control arm (36% vs 28%). Daver et al. and Vey et al. both studied lirilumab (anti-KIR antibody), but Daver et al. reported an ORR of 14% (5/32) in the lirilumab + azacytidine arm. In a separate study, Daver et al. administered nivolumab (anti-PD1 antibody) + azacytidine and noticed an ORR of 33% (23/70). Zeidan et al. reported that the durvalumab (anti-PD-L1 antibody) + azacytidine arm had a lower ORR than the control arm (31% vs 35%). A summary of the adverse events was provided below (Table). Conclusions: Antibody-based therapies are showing great promise for the treatment of AML but are associated with various adverse effects. More prospective clinical trials are needed to further assess the long-term benefits of such medications.[Table: see text]
Utility and timeliness of somatic genetic testing for patients enrolled in the molecular screening and therapeutics (MoST) study at Princess Alexandra Hospital (PAH).
Authors: Benjamin Watson, Melissa Arneil, Paul Leo, Kenneth John O'Byrne, Victoria Atkinson
Journal: Journal of Clinical Oncology (2022)

e15039 Background: Next generation sequencing (NGS) technologies are increasingly employed to deliver optimal precision therapy for patients with cancer. The Molecular Screening and Therapeutics (MoST) study led by Prof David Thomas, Garvan Institute, Sydney, Australia, was established to identify patients for enrolment into clinical trials and for targeted or immune therapies not routinely indicated for their illness, specifically focusing on those with rare or neglected malignancies or with more common malignancies that had completed standard therapy. Methods: 111 patients were enrolled at the PAH between 1/5/2020 and 31/5/2021. Of these the results of the first 100 patients with complete medical records and sufficient tissue for NGS analysis are reported. Sources included electronic medical record, cancer state-wide database and the Molecular Tumor Board reports. The NGS Illumina TSO500 platform was employed for genetic testing. Determining utility of the results/reports included analyzing the proportion of patients with clinically relevant mutations detected, treatment recommendations, clinical trial recommendations and clinical trial enrolments. The timeframe from enrolment to results/recommendations conveyed to the patient was recorded. Demographic data was collected at enrolment. The final date of data collection was 31/12/2021, ensuring a minimum of six months follow-up. Local ethical regulations were complied with. Results: The study included 51 men and 49 women, ECOG 0-1, median age 57 years (range 21 – 84 years). Gastrointestinal malignancies were the most common, 31 patients, followed by sarcoma, 16, and breast cancer, 14. At enrolment, 64 patients were receiving chemotherapy, with the lines of treatments received ranging from 0 – 7, mean of 2.6. Mutations were detected in the following number of specimens: Tier 1A - 21, Tier 2C - 27, Tier 2D - 69 and Tier 3 - 69. High tumor mutational burden, defined as &gt;10Muts/Mb, was present in 12 specimens and potential germline mutations were detected in 22 patients. There were 34 treatment recommendations and 27 clinical trial recommendations with 14 patients enrolled in clinical trials. The mean timeframe from enrolment to the result of testing being conveyed to the patient was 85.1 days. The overall median survival was 9.72 months. Conclusions: Results demonstrate that somatic genetic testing generates clinical trial, treatment and genetics health recommendations for a significant number of patients with 1:7 being recruited into clinical trials. Median length of time between recruitment and delivery of results to the patient was almost 3 months, which will improve through streamlining of clinical and logistical processes and advances in testing technologies, ensuring timely results for clinicians and their patients.
Camrelizumab plus apatinib in patients with recurrent and/or metastatic nasopharyngeal carcinoma: A single-arm, multicenter, phase 2 trail.
Authors: Yunyan Mo, Yufei Pan, Bin Zhang, Jian Zhang, Zhengchun Liu, Meiqing Luo, Yixin Su, Wei Jiang
Journal: Journal of Clinical Oncology (2022)

e18025 Background: Our previous study demonstrated that apatinib has preliminary clinical benefit in recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC). Preclinical studies showed the combination of immune checkpoint inhibitors and antiangiogenic drugs produces a synergistic effect in anti-tumor activity. This phase 2 trail evaluated the efficacy and safety of camrelizumab combined with apatinib in patients with RM-NPC. Methods: In this study, patients with RM-NPC received 250 mg apatinib orally once per day plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed according to RECIST version 1.1. The key secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The study is registered with. Results: From January 14, 2021 to September 15, 2021, 26 patients with RM-NPC were enrolled in this clinical study with median follow-up duration of 8 months (range:4-12 months). The ORR was 38.5% (10/26), and the DCR was 61.5% (16/26). Median PFS (mPFS) was 6 months. Median OS was not reached. Of the 26 patients, 6 patients (23.1%) had treatment-related grade 3 or 4 adverse events, including anemia(7.7%), stomatitis(3.8%), headache(3.8%), pneumonia(3.8%) and myocarditis(3.8%). No treatment-related deaths occurred in this trial. Conclusions: Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with RM-NPC, and the mPFS by this combination regimen was longer than our previously reported mPFS by apatinib monotherapy. Larger randomized trials to evaluate this new combination strategy are warranted. Clinical trial information: NCT04350190. [Table: see text]
Electron flash-RT program in clinical setting for human translation.
Authors: Rongxiao Zhang, Mahbubur Rahman, Petr Bruza, Charles R. Thomas, Lesley A. Jarvis, P. Jack Hoopes, David J. Gladstone, Brian W. Pogue
Journal: Journal of Clinical Oncology (2022)

e13596 Background: A FLASH-RT program was established at Dartmouth-Hitchcock Medical Center in minimally-modified clinical setting by joint efforts of biomedical engineering, radiation oncology, radiation biology and medical physics teams. Various projects on dosimetry, chemical sensing, molecular profiling, software/hardware development, and translational studies have been conducted. The aim is to share logistical considerations and experience on running a FLASH-RT program to support institution-wide academic activities with an ultimate goal of treating human patients with FLASH-RT in 2022. Methods: A linac was converted in the clinical setting by qualified engineers to deliver an ultra-high dose rate (UHDR) electron beam. Routine safety and dosimetry checks were done by physicists for every reversible conversion. Long-term record-keeping and retrospective surveys were carried out to demonstrate the feasibility, safety, stability and accuracy of this dual-purpose (FLASH and conventional RT) approach. Comprehensive failure mode and effects analysis (FMEA) has been completed to systematically evaluate safety related considerations. A treatment planning system (TPS) has been developed in Varian Eclipse to facilitated comparative studies. The FLASH-capable linac has been utilized as shared resource to support institution-wide academic activities as well as normal clinical treatments. Results: With its safety (no accident or FLASH-related malfunction), flexibility (&gt; 100 conversions in 2 years), reliability (̃6000 hours in flash mode and ̃5x10 5 Gy accumulative dose delivered at isocenter) and accuracy (̃5% conversion-to-conversion variations) demonstrated by commissioning, long-term user experience and comprehensive FMEA analysis, the FLASH-RT platform has been actively utilized for researches in six major categories 1) FLASH beam dosimetry; 2) real-time beam delivery monitoring and control; 3) oximetry and chemical sensing; 4) preclinical/translational small/large animal treatment with tumor control and normal tissue complication endpoints, 5) treatment plan and delivery optimization; 6) the design of phase I/II trials. Key findings in each category will be reported. Conclusions: A FLASH-RT program in clinical setting is established at Dartmouth with joint efforts, promoting collaborative projects to advance FLASH-RT to clinical treatment. The system has been reliably utilized for over two years for mechanistic as well as translational studies and support a phase I/II trial treating cutaneous lymphoma with eFLASH-RT.